The use of treosulfan in conditioning for haematopoietic stem cell transplantation in children with primary immunodeficiency

Abstract

Primary Immunodeficiencies (PIDs) are inherited disorders that lead to defects in the development and/or function of the immune system. The number of disorders that can be treated by haematopoietic stem cell transplantation (HSCT) has increased rapidly with the advent of next generation sequencing. The methods used to transplant children with PID have improved dramatically over the last 20 years. The introduction of reduced toxicity conditioning is an important factor in the improved outcome of HSCT. Treosulfan has myeloablative and immunosuppressive properties, enabling engraftment with less toxicity than traditionally used doses of busulfan. The use of treosulfan in conditioning prior to HSCT for children with PID is reported in this thesis. Six published works are presented. The first 2 provide background with up to date information on HSCT and conditioning regimens in children with PID. The increased use of low toxicity treosulfan-based combinations is demonstrated in published paper PP3 which is the largest published series to date of patients with non-malignant disorders who received treosulfan-based conditioning across Europe. The place of treosulfan in conditioning patients specifically with Chronic Granulomatous Disease from centres worldwide is presented in PP4. Close collaboration with Great Ormond Street Hospital, London has led to rigorous monitoring and step by step improvements in the approach to transplant using treosulfan, published in Supplementary paper 1, followed by PP5 and culminating in a prospective pharmacokinetic study presented in PP6, which is the first study to demonstrate an association with high area under the concentration curve (AUC) and increased mortality, and low AUC and poor engraftment. For each manuscript I present an overview of the study, what was known before, and what the study added to the literature, my contribution to the work and a short discussion of the strengths and limitations. Treosulfan has been established as a safe and effective agent for conditioning children with PID prior to HSCT. It is firmly incorporated into the conditioning guidelines of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation. The works presented in this thesis demonstrate the contribution that I have made to the field, and pave the way for future research. It is likely that individualized dosing, not just of treosulfan, but of all agents used in conditioning regimens, will be developed and implemented. This will lead to a reduction in unwanted variability in drug exposure, leading to more predictable and adjustable exposure, and improved outcome of HSCT, with fewer late adverse effects and improved quality of life. Such conditioning regimens can be used as the basis to study the need for additional agents in certain disorders, the dosing of individual cellular components within grafts and effects of adjuvant cellular or immunotherapy post-transplant.